Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:16][CH:17]1[CH2:19][O:18]1>CCO>[CH:7]([N:8]1[CH2:19][CH:17]([OH:18])[CH2:16]1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: ClCC1CO1
Solvent: CCO
Product: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
A solution of diphenylmethanamine (16.2 g, 88.5 mmol) and 2-(chloromethyl)oxirane (8.19 g, 88.5 mmol) in dry EtOH was stirred at RT for 48 hours and then heated at reflux for 48 hour. The reaction mixture was concentrated under reduced pressure and the residue was stirred in acetone (300 mL) for 30 min. The resulting off-white solid precipitate was filtered, washed with cold acetone (100 mL), and dried in vacuo to obtain 1-benzhydrylazetidin-3-ol as white crystalline solid (11.0 g, 51% yield); LC-MS: 240.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[C:23]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:22][C:21](F)=[CH:20][N:19]=1)=[O:17].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CCOC(C)=O>[F:35][C:33]1[CH:32]=[C:4]([CH:3]=[C:2]([F:1])[CH:34]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[C:23]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:22][C:21]([N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)=[CH:20][N:19]=1)=[O:17]
Reactant: CN1CCNCC1
Reactant: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1ncc(F)cc1NC1CCOCC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2cnc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1

Procedure:
A solution of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-5-fluoro-3-(tetrahydro-2H-pyran-4-ylamino)pyridine-2-carboxamide (925 mg, 1.92 mmol) and N-methylpiperazine (20 mL) was stirred at 60° C. for 48 hours. The reaction mixture was then diluted with EtOAc and washed with NaHCO3 sat.sol. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography on silica gel using DCM/EtOH/NH3 5N in MeOH 100:5:0.5 as the eluant, affording 600 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([N:14]([CH2:34][CH2:35][CH3:36])[CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C@H:24]([CH2:28][C:29]([O:31]CC)=[O:30])[CH2:23][CH2:22]4)=[N:12][CH:13]=2)[S:5][C:6]=1[CH3:7].CO.O.[Li+].[OH-]>C1COCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([N:14]([CH2:34][CH2:35][CH3:36])[CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C@H:24]([CH2:28][C:29]([OH:31])=[O:30])[CH2:23][CH2:22]4)=[N:12][CH:13]=2)[S:5][C:6]=1[CH3:7]
Reactant: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC)c1ccc(-c2nc(C)c(C)s2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)O)c1ccc(-c2nc(C)c(C)s2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.8 %

Procedure:
To a solution of ethyl ((1S)-5-{3-[[5-(4,5-dimethyl-1,3-thiazol-2-yl)-2-pyridinyl](propyl)amino]-propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 267) (70 mg, 0.15 mmol) in a mixture of THF (2 mL), methanol (2 mL), and water (1 mL) was added LiOH (40 mg, 1.74 mmol). The mixture was stirred at rt for 18 h and then concentrated under reduced pressure. The residue was taken up in water and acidified using H3PO4 (5% solution in water). The aqueous phase was extracted with ethyl acetate, and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the product (56 mg, 86%). 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, 1H), 7.80 (d, 1H), 7.06 (d, 1H), 6.79 (d, 1H), 6.71 (dd, 1H), 6.56 (d, 1H), 3.95 (t, 2H), 3.62 (t, 2H), 3.44-3.25 (m, 3H), 2.81-2.62 (m, 3H), 2.30-2.23 (m, 8H), 1.99-1.96 (m, 2H), 1.65-1.53 (m, 3H), 0.87 (t, 3H); LC-MS: RT=2.73 min, (M+H)+ 480.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:5]([O:8][CH:9]2[CH2:12][CH:11]([C:13]([C:15]3[N:19](COC)[C:18]4[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=4[N:16]=3)=[O:14])[CH2:10]2)=[N:6][CH:7]=1.Cl>C1COCC1>[NH:16]1[C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[N:19]=[C:15]1[C:13]([C@H:11]1[CH2:10][C@@H:9]([O:8][C:5]2[C:4]([CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[CH2:12]1)=[O:14].[NH:16]1[C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[N:19]=[C:15]1[C:13]([C@H:11]1[CH2:10][C@H:9]([O:8][C:5]2[C:4]([CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[CH2:12]1)=[O:14]
Reactant: COCn1c(C(=O)C2CC(Oc3ncc(F)cc3C3CCOCC3)C2)nc2ccccc21
Agent: Cl
Solvent: C1CCOC1
Product: O=C(c1nc2ccccc2[nH]1)[C@H]1C[C@@H](Oc2ncc(F)cc2C2CCOCC2)C1
Product: O=C(c1nc2ccccc2[nH]1)[C@H]1C[C@H](Oc2ncc(F)cc2C2CCOCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclobutyl}-(1-methoxymethyl-1H-benzoimidazol-2-yl)-methanone (1.2 g) in THF (20 mL) at RT was added concentrated HCl (20 mL). The reaction mixture was stirred at RT for 1 h and then heated to 60° C. for 6 h. The mixture was partially concentrated, neutralized with saturated NaHCO3 and diluted with EtOAc. The aqueous phase was extracted with EtOAc (2×10 mL) and the combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated to get a residue, which was purified by flash column chromatography on silica gel (5% to 30% EtOAc in DCM) gave cis-(1H-benzoimidazol-2-yl)-{3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclobutyl}-methanone and trans-(1H-benzoimidazol-2-yl)-{3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclobutyl}-methanone (196 mg) as white solid. [M+1] 396 each. IC50 (uM) 0.00003 (cis) and 0.0005 (trans).
Reaction SMILES: CO[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10].[OH:19][C@H:20]([C@@H:31]([NH:39][C:40](=[O:59])[C@H:41]([CH2:55][C:56](=[O:58])[NH2:57])[NH:42][C:43]([C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:46]=1)=[O:44])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:21][N:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:23].CN([C:63]([O:67]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1CCOCC1.CN(C=O)C.C(Cl)Cl>[OH:19][C@H:20]([C@@H:31]([NH:39][C:40](=[O:59])[C@H:41]([CH2:55][C:56](=[O:58])[NH2:57])[NH:42][C:43]([C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:46]=1)=[O:44])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:21][N:22]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH:23][C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:9]([O:8][CH2:7][CH:6]([O:67][CH3:63])[O:5][CH2:4][CH3:3])=[O:10]
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccccc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COCCOCCOC(=O)N[C@H](C(=O)O)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(COC(=O)N[C@H](C(=O)NN(Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1)C(C)C)OC

Procedure:
Analogously to Example 111, 52 mg (0.198 mmol) of N-(2-(2-methoxy-ethoxy)-ethoxy)carbonyl-(L)-valine (Example 82a)) and 100 mg (0.180 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(quinoline-2-carbonyl)-(L)-asparaginyl)amino-4-phenyl-butyl]-1-[phenylmethyl]-hydrazine in 1.8 ml of 0.3M NMM/DMF are reacted with 75.1 mg (0.198 mmol) of HBTU. The evaporation residue is taken up in methylene chloride and washed with 2 portions of 10% citric acid solution, water, saturated NaHCO3 solution and brine. The aqueous phases are extracted a further twice with methylene chloride and the combined organic phases are dried with Na2SO4 and concentrated by evaporation. Column chromatography (SiO2, methylene chloride/methanol 19:1) yields the title compound: TLC Rf (J')=0.08; tRet (V)=13.5 min; FAB-MS (M+H)+ +800.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][NH2:13].[CH:14]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1>>[Cl:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[C:29]([C:28]1[CH:31]=[CH:32][C:25]([O:24][CH:21]3[CH2:22][CH2:23][N:18]([CH:14]4[CH2:17][CH2:16][CH2:15]4)[CH2:19][CH2:20]3)=[CH:26][CH:27]=1)[N:13]([CH3:12])[C:4]2=[O:6]
Reactant: O=Cc1ccc(OC2CCN(C3CCC3)CC2)cc1
Reactant: CN
Reactant: Nc1c(Cl)cccc1C(=O)O
Product: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2c(Cl)cccc2c1=O

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 2-amino-3-chlorobenzoic acid, methylamine and 4-[(1-cyclobutyl-4-piperidinyl)oxy]benzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][NH:17][CH2:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:6][CH:5]=1.[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]2[CH:22]=[CH:21][C:20]3[CH2:19][CH2:18][N:17]([CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:16][CH2:15][C:14]=3[CH:13]=2)=[CH:8][CH:9]=1
Reactant: O=C1CCCC1
Reactant: COC(=O)c1ccc(COc2ccc3c(c2)CCCNC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(2,3,4,5-Tetrahydro-1H-benzo[c]azepin-7-yloxymethyl)-benzoic acid methyl ester (D4) (2.83 g, 9.1 mmol) and cyclopentanone (1.6 ml, 18.2 mmol) were dissolved in dichloromethane (30 ml) and acetic acid (0.5 ml). Sodium triacetoxy borohydride (3.85 g, 18.2 mmol) was added and the solution was stirred at room temperature for 4 hours. The reaction mixture was washed with a saturated solution of sodium carbonate, the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (E88); MS (ES+) m/e 380 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-:15])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[N+]([O-])=O.[OH-].[Na+].O.[CH2:19]([OH:22])[CH:20]=[CH2:21]>>[CH2:19]([O:22][C:11]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N+:4]([O-:15])=[CH:3][C:2]=1[CH3:1])[CH:20]=[CH2:21]
Reactant: Cc1c[n+]([O-])c2c(c1[N+](=O)[O-])CCCC2
Reactant: C=CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCOc1c(C)c[n+]([O-])c2c1CCCC2
Reaction time: 3 h

Procedure:
2.0 Grams of 3-methyl-4-nitro-5,6,7,8-tetrahydroquinoline-N-oxide was dissolved in allyl alcohol. Then 0.6 g of sodium hydroxide was added thereto, and the mixture was stirred at 70°-80° C. for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, to the residue thus obtained was added water, and was extracted with chloroform. The chloroform layer was washed with an aqueous solution saturated with sodium chloride, then dried with anhydrous magnesium sulfate. Chloroform was removed by evaporation under reduced pressure to obtain 1.4 g of 4-allyloxy-3-methyl-5,6,7,8-tetrahydroquinoline-N-oxide in the form of brown oily substance.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][C:3]=1[F:19].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[C:3]([F:19])[CH:4]=2)[N:9]=1
Reactant: Fc1cc2c(N3CCOCC3)nc(Cl)nc2cc1Br
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc2c(N3CCOCC3)nc(Cl)nc2cc1-c1cccnc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a 50 mL round bottom flask, 7-bromo-2-chloro-6-fluoro-4-morpholin-4-yl-quinazoline (200 mg, 0.0005764 mol), pyridine-3-boronic acid (63.3 mg, 0.0005188 mol), sodium carbonate (152.6 mg, 0.001441 mol), DMF (10 mL) and water (5 mL) were added and degassed the reaction vessel with nitrogen for 5-10 min. To the same reaction mixture, Pd(PPh3)2Cl2 (20.1 mg, 0.0000288 mol) was added and again degassed with N2 for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 2% MeOH in chloroform) to yield the desired product (180 mg, 91%). 1H NMR (300 MHz, CD3OD): δ 8.27-8.30 (m, 1H), 8.21-8.25 (m, 1H), 8.15-8.18 (m, 1H), 7.91-7.92 (m, 1H), 7.74-7.78 (m, 1H), 7.47-7.51 (m, 1H), 3.99-4.01 (m, 4H), 3.85-3.88 (m, 4H); LC-MS (ESI): Calculated mass: 344.1; Observed mass: 344.9 [M+H]+ (RT: 1.3 min).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH3:25])[CH:20]=2)[CH:15]([C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[CH:14]1C(O)=O.N1C=CC=CC=1.S(Cl)(Cl)=O.SC1C=CC=C[N+]=1[O-]>ClCCl>[OH:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH3:25])[CH:20]=2)[CH:15]([C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[CH2:14]1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(C(=O)O)C2c1ccc2c(c1)OCO2
Agent: [O-][n+]1ccccc1S
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1O)CC2c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 46 %

Procedure:
A solution of (1RS, 2SR, 3RS)-3-[2-(methoxymethoxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (0.2 g, 0.39 mmol) in dichloromethane (4 ml) and pyridine (28 μl, 1.6 mmol) was cooled to 0° C. under argon. To this solution was added thionyl chloride (60 μl , 0.8 mmol). The mixture was allowed to warm to ambient temperature over 20 min. and the volatiles removed in vacuo. The residue was redissolved in toluene and evaporated in vacuo (twice). The residue was dissolved in dichloromethane (4 ml) and triethylamine (250 μl) added. To this solution at room temperature under argon was added 2-mercaptopyridine-N-oxide (120 mg, 0.8 mmol) dissolved in dichloromethane (1 ml). After stirring for 20 min at room temperature t-butylthiol (450 μl, 4 mmol) was added and the mixture irradiated for 20 min (150 watt spotlight). The volatiles were removed in vacuo and the product partitioned between ethyl acetate and 3M-aq. HCl. The organic extract was washed with water, sat aq. NaHCO3 solution and finally brine. After drying (MgSO4 anhydrous), the product was filtered and evaporated Purification by column chromatography gave the title compound (0.075 g, 41%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:17][O:16][CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[O:16]1[CH2:17][CH:14]([N:11]2[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C2COC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(C2COC2)CC1
Yield: 100.9 %

Procedure:
To a solution of (1-oxetan-3-yl-piperidin-4-yl)-carbamic acid tert-butyl ester (134 mg, 0.52 mmol) in dichloromethane (2 mL) was added TFA (2 mL). After 15 minutes at ambient temperature the reaction mixture was concentrated in-vacuo and the residue loaded onto a 5 g SCX-2 cartridge which was washed with methanol, then 2N ammonia in methanol. Concentration of the combined basic fractions in-vacuo afforded the title compound as a colourless gum (82 mg, 100%). 1H NMR (400 MHz, CDCl3): 4.63-4.63 (m, 4H), 3.47-3.45 (m, 1H), 2.69-2.68 (m, 3H), 1.90-1.81 (m, 4H), 1.41-1.40 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25](OCC)=[O:26])=[CH:20][CH:19]=3)[CH:9]=2)=[CH:4][CH:3]=1.NC1C=CC(CCO)=CC=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][OH:26])=[CH:22][CH:23]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3ccc(Cl)cc3)nc3c2CCC3)cc1
Agent: Nc1ccc(CCO)cc1
Product: Cl
Product: OCCc1ccc(Nc2cc(-c3ccc(Cl)cc3)nc3c2CCC3)cc1
Yield: 39.3 %

Procedure:
Following General Procedure B2, ethyl 2-(4-((2-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-yl)amino)phenyl)acetate (0.100 g, 0.38 mmol) was reacted with 4-aminophenethyl alcohol (0.078 g, 0.57 mmol) followed by the formation of the hydrochloride salt to afford the title compound (0.030 g, 30%) as a yellow solid. MW=401.33. 1H NMR (DMSO-d6, 300 MHz) δ 13.99 (s, 1H), 9.77 (s, 1H), 7.82-7.73 (m, 2H), 7.70-7.62 (m, 2H), 7.39-7.27 (m, 4H), 6.95 (s, 1H), 3.64 (t, J=6.8 Hz, 2H), 3.15 (t, J=7.7 Hz, 2H), 2.91 (t, J=7.6, 2H), 2.76 (t, J=7.6 Hz, 2H), 2.30-2.15 (m, 2H); APCI MS m/z 365 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[CH2:16][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][C@H:9]1[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[CH3:24][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[C:1]([N:8]1[CH2:16][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][C@@:9]1([CH3:24])[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)[C@]1(C)C[C@@H](c2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-BOC-4-(S)-phenyl-(L)-proline, methyl ester from Step A (2.0 g, 6.56 mmol) in anhydrous THF (20 mL) at −78° C. was added over a 30 min period 1M LiHMDS in hexanes (9.83 mL, 9.83 mmol) and allowed to stir for 30 mins at −78° C. The reaction was then allowed to stir for 1 hr at 0° C. The reaction was then cooled to −78° C. and MeI (4.65 g, 32.79 mmol) was added dropwise. The reaction was allowed to warm to rt overnight. The reaction was quenched with NH4Cl. The organic layer was collected and washed with 1M HCl, NaHCO3, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluted with 75% Et2O/hexanes to give 1.85 g of desired product.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7](B(O)O)[CH:6]=1.Br[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[CH3:26])[CH:6]=1
Reactant: COCOc1ccc(C)c(B(O)O)c1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(O)ccc2C)c(C)c1

Procedure:
In a manner similar to that of Example 11(d), by reaction of 3.7 g (18.8 mmol) of 4-methoxymethoxy-1-methylbenzene-2-boronic acid with 3.9 g (17 mmol) of methyl 4-bromo-3-methylbenzoate, 17 mL of 2.0M potassium carbonate solution and 1 mg (0.85 mmol) of tetrakis(triphenylphosphine)palladium, followed by deprotection in methanol, the desired product is obtained in the form of a thick, colourless oil (m=2.87 mg; Y=51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]([O:12]C)=[O:11])=[N:7][C:8]=1[CH3:9].O.[Li+].[OH-].C(OCC)(=O)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[N:7][C:8]=1[CH3:9]
Reactant: COC(=O)c1ccc(OC)c(C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To methyl 5-methoxy-6-methyl-pyridine-2-carboxylate (1.00 g, 5.52 mmol) was dissolved in tetrahydrofuran (5.4 mL) was added water (2.7 mL) and LiOH (132.2 mg, 5.52 mmol). The mixture was stirred at room temperature overnight, then at 60° C. for 1.5 hours. Additional LiOH in water (2.76 mL of 2 M, 5.519 mmol) was added and the reaction was heated at 60° C. for 0.5 hours. The mixture was poured into water (5 mL) and ethyl acetate (15 mL) and the layers were separated. The aqueous layer was acidified to pH 4 with 2 N HCl and was extracted with ethyl acetate (7×25 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield 5-methoxy-6-methylpicolinic acid (0.71 g, 77%) as a white solid. 1H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 3.89 (s, 3H), 2.40 (s, 3H). ESI-MS m/z calc. 167.1, found 168.3 (M+1)+; Retention time: 0.19 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Mg].[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][C@H:17]([CH3:26])[C:18](N1CCOCC1)=[O:19].[Cl-].[NH4+]>O1CCCC1.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:18](=[O:19])[C@H:17]([O:16][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)[CH3:26])=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: C[C@@H](OC1CCCCO1)C(=O)N1CCOCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](OC1CCCCO1)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 235.1 %

Procedure:
To a solution of 1-bromo-4-chlorobenzene (20 g) in tetrahydrofuran (260 ml) was added magnesium (turnings, 7.47 g). The mixture was vigorously stirred at room temperature. When the temperature of the mixture reached 40° C., the reaction vessel was cooled in a water bath. A solution of 1-bromo-4-chlorobenzene (38.9 g) in tetrahydrofuran (90 ml), was added dropwise to the mixture at 34°-40° C., followed by stirring for an hour at 30° C. To the mixture was added dropwise a solution of 4-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl] morpholine (60 g) in tetrahydrofuran (60 ml) over the period of 15 minutes at 0° C. The mixture was stirred for 3 hours at room temperature. To the reaction mixture were added a saturated aqueous ammonium chloride solution (120 ml) and water (100 ml). The mixture was extracted with ethyl acetate (500 ml). The organic layer was washed with water, dried over magnesium sulfate and distilled under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 900 g, eluent: hexane/ethyl acetate=30:1→10:1) to give (2R)-4'-chloro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (66 g) as a pale yellow oily substance.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][C:9](=O)[CH2:10][C:4]2=[N:3][N:2]=1.CO>O1CCCC1>[CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][CH2:9][CH2:10][C:4]2=[N:3][N:2]=1
Reactant: O=C1Cc2nncn2-c2ccccc2N1
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc2c(c1)NCCc1nncn1-2
Temperature: 25 °C

Procedure:
A mixture of 7.0 g of 5,6-dihydro-4H-[1,2,4]triazolo-[4,3-a][1,5]benzodiazepin-5-one in 25 ml of tetrahydrofuran is added 9 ml of 10M boranedimethylsulfide in tetrahydrofuran. The mixture is refluxed for 6 hours, cooled to room temperature and 25 ml of methanol added dropwise. The volatiles are removed under vacuum and to the residue is added 100 ml of 2N sodium hydroxide. The mixture is refluxed for 5 hours, chilled and extracted with dichloromethane. The extract is washed with 2N citric acid, water and dried (Na2SO4). The solvent is removed under vacuum to give a solid. The solid is purified by chromatography on silica gel to give the desired product.